Kill the Real with the Fake: Eliminate Intracellular Staphylococcus aureus Using Nanoparticle Coated with Its Extracellular Vesicle Membrane as Active-Targeting Drug Carrier

Abstract

Staphylococcus aureus bacteremia is one of the most serious bacterial infections worldwide. Most complications of S. aureus bacteremia arise because the pathogen can survive inside host phagocytes, especially macrophages, which makes elimination of intracellular S. aureus key to clinical success. Unfortunately, most antibiotics have poor cellular penetration capacity, which necessitates intracellular delivery of antibiotics. We herein use nanoparticle coated with membrane of extracellular vesicle secreted by S. aureus (i.e., NP@EV) as active-targeting antibiotic carrier, with counterparts coated with PEGylated lipid bilayer (i.e., NP@Lipo; PEG = poly(ethylene glycol)) or with membrane of outer membrane vesicle secreted by Escherichia coli (i.e., NP@OMV) included as controls. NP@EV is internalized at higher efficiency by S. aureus-infected macrophage than by nai ̈ve counterpart, whereas NP@Lipo and NP@OMV are not; instead, NP@OMV, but neither NP@EV nor NP@Lipo, is internalized at higher efficiency by E. coli-infected macrophage than by nai ̈ve counterpart. Moreover, when injected intravenously into mouse models, NP@EV, but neither NP@OMV nor NP@Lipo, exhibits significantly higher accumulations within four major organs (kidney, lung, spleen, and heart) bearing metastatic S. aureus infections than within healthy counterparts. These observations suggest that EV membrane coating of NP@EV endows the particle with active targeting capacity both in vitro and in vivo. As a result, when preloaded with antibiotics and intravenously administered to alleviate metastatic infection in S. aureus bacteremia-bearing mouse model, NP@EV confers its cargoes with strikingly improved efficacy; in doing so, NP@EV is significantly more efficient than both NP@Lipo and NP@OMV in kidney and lungwhich bear the highest metastatic bacterial burden and represent most common sites for S. aureus infection, respectively. Such an active-targeting delivery platform may have implications in promoting clinical success on intracellular pathogen-associated complications.

Recent Advances in Polymeric Nanoparticle-Encapsulated Drugs against Intracellular Infections

“…In this sense, there exist a plethora of publications regarding nanoencapsulation of antimicrobials in PNs to treat intracellular infections using diverse approaches to promote endocytosis of the PNs and the killing of pathogens by antimicrobials. These strategies include PNs using polymers as a delivery platform, PNs in which the polymer itself possesses antimicrobial properties and novel approaches such as hybrid platforms, smart materials, ligand-based functionalized PNs, lipid polymer hybrid nanoparticles and antimicrobial photodynamic therapy ( Figure 5 ) [ 4 , 46 , 190 , 191 , 192 , 193 , 194 , 195 , 196 , 197 ].…”

Multifunctional lipid-based nanocarriers with antibacterial and anti‐inflammatory activities for treating MRSA bacteremia in mice

“…4a). Nanomedicine has been widely used due to its success in eradicating drug-resistant bacteria in vitro or in vivo [27][28][29][30][31][32]. We focused on the effect of nanocarriers encapsulating two drugs on the treatment of the bacteremia induced by MRSA.…”

Targeted Therapeutic Strategies in the Battle Against Pathogenic Bacteria

“…Additionally, other natural cell membranes can also be utilized. The membrane of extracellular vesicles secreted by S. aureus was reported to be applied to enclose nanoparticles as a natural guide ( Gao et al, 2019 ). This well-designed complex therefore exhibited high specificity and efficacy against S. aureus infection in mouse models.…”